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Background: Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT). Methods: Studies used various endothelial transgenic and deletion mutant ApoE −/− mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT. Results: Enhancing insulin’s actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester ( L -NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO’s action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE − /− mice. Conclusions: Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.

Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce renal and heart failure (HF) events in people with and without diabetes. Although their glycemic efficacy is dependent on kidney function, it remains unclear to what extent baseline kidney function influences the magnitude of SGLT2i cardiorenal effects. Methods We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials testing the effects of SGLT2i on renal and CV outcomes (PROSPERO registration number CRD42022325976). Efficacy outcomes, stratified by five estimated glomerular filtration rate (eGFR) categories, included progression of renal disease (as defined in each trial), a composite HF outcome (defined as CV death or hospitalization/urgent visit for HF), and all-cause mortality. Results Eleven trials testing five SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) in 77,541 participants were included. The majority of participants (39.8%) had eGFR values between 60 and 90 ml/min/1.73m2, with only 1.3% having advanced kidney disease (eGFR between 20 and 30 ml/min/1.73m2). Overall, SGLT2i reduced the risk of renal disease progression by 41% (HR 0.59, 95%CI 0.54–0.65, p Conclusions SGLT2i reduce risk of renal disease progression and HF outcomes for all eGFR subgroups. However, the opposite trends for the influence of baseline kidney function between renal and HF outcomes suggest different SGLT2i mechanisms for renal and cardiac protection.

Effects of novel glucose-lowering agents on cardiac autonomic function and structure in type 2 diabetes Ilaria Cavallari, Ernesto Maddaloni, Francesco Veneziano, Carla Indennidate, Maria Valeria Giaccari, Dario Tuccinardi, Silvia Pieralice, Nicola Napoli, Raffaella Buzzetti, Francesco Grigioni Background Novel glucose-lowering agents, such as sodium glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have the potential to reduce major adverse cardiovascular events among people with type 2 diabetes. However, mechanisms behind their cardiovascular protection and the implications of positive chronotropic effects of GLP-1 receptor agonists are not fully understood. Purpose To elucidate and compare the effects of novel glucose-lowering agents on cardiac autonomic function and structure. Methods This prospective observational study included subjects with type 2 diabetes and either a history of established cardiovascular disease or multiple risk factors and early initiation (within 2 weeks) of a SGLT-2 inhibitor or a GLP-1 receptor agonist on top of standard of care. Patients were followed for a median of 2 months. As per study protocol, background medical therapy should have remained stable for the entire duration of the study. Cardiac autonomic reflex tests (heart rate response to a deep breathing and to standing) and echocardiography were performed in all patients at baseline and at the end of follow-up. Endpoints were changes from baseline of E/I ratio, 30:15 ratio and indices of cardiac structure and function. Results A total of 37 patients completed follow-up, of whom 20 were on SGLT-2 inhibitors and 17 on GLP-1 receptor agonists. Mean age was 69 years, mean disease duration was 14 years and mean HbA1c value was 7.5%. Cardiac autonomic dysfunction, defined as at least an abnormal test, was found in 19% of patients (n=7). At a median follow-up of 2 months, there were no differences from baseline in heart rate response to a deep breathing test (p=0.92) and to standing (p=0.86). No differences were found when patients were stratified according to drug class. Among echocardiographic parameters, significant reductions of left ventricular mass (300.5±73.3 vs 280.4±68.3 g/m2, p=0.048) and left atrial volume (61.3±29.4 vs 54.7±18.0 ml, p=0.034) were found with no interaction by drug class. Left ventricular end-diastolic and systolic volumes, ejection fraction, filling pressures and pulmonary artery pressure did not substantially change. Conclusions In a population of patients with type 2 diabetes, short-term treatment with novel glucose-lowering agents significantly reduced left ventricular mass and left atrial volume but did not affect cardiac autonomic function.

Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated to reduce heart failure (HF) and renal outcomes irrespective of diabetes status. The cardiovascular efficacy and the mortality benefit of these agents in patients without HF and across the spectrum of left ventricular ejection fraction (EF) are a matter of debate. Methods This study-level meta-analysis included 11 controlled randomized trials and 76,520 patients randomized to a SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) or placebo in different clinical settings including diabetes, HF with reduced or preserved EF and chronic kidney disease. Data were stratified by history of HF, HF with reduced EF (≤40%), mid-range EF (40-49%) and preserved EF (≥50%). The incidence of the following outcomes, when available, was evaluated: HF composite outcome, defined as cardiovascular death or hospitalization/urgent visit for HF, its individual components and all-cause mortality. An additional sensitivity analysis tested the efficacy of SGLT-2 inhibitors in patients with extremely reduced EF (≤30%). Results Overall, there were 22,653 patients with HF (33.8%) and 44,304 patients without HF (66.2%). In patients without history of HF, SGLT-2 inhibitors significantly reduced the risk of HF outcomes (HR 0.76, 95% CI 0.68-0.86) and all-cause mortality (HR 0.84, 95% CI 0.73-0.95). In patients with HF, a significant reduction in the composite of cardiovascular death and HF events was consistently observed in those with reduced EF (HR 0.71, 95% CI 0.65-0.78), mid-range EF (HR 0.68, 95% CI 0.57-0.81) and preserved EF (HR 0.78, 95% CI 0.69-0.89; Figure). There was a significant reduction in all-cause mortality also in patients with HF treated with SGLT-2 inhibitors (HR 0.87, 95% CI 0.80-0.95). Conclusions SGLT-2 inhibitors demonstrated cardiovascular and mortality benefits irrespective from history of HF and across the spectrum of left ventricular EF.

Diabetes mellitus worsens the prognosis of SARS-CoV-2 infection, and vaccination has been the major tool for reducing the risk of hospitalisation, and mortality. The primary aim of this study was to evaluate the response to the SARS-CoV-2 vaccine in subjects with diabetes and controls. Differences between type 1 (T1D) and type 2 (T2D) diabetes and clinical determinants of vaccination response were also evaluated.128 subjects with diabetes (60 with T1D and 62 with T2D) and 202 subjects acting as controls who completed a full vaccination cycle with two doses of mRNA vaccine were enroled. People with previous SARS-CoV-2 infection were excluded. Antibodies (Ab) directed against the spike protein of the SARS-CoV-2 were evaluated at one and 6 months after vaccination.In the whole cohort, the Ab level was higher among women than in men (p = 0.011) and negatively correlated with age (rho = -0.155, p = 0.005). Subjects with diabetes showed decreased levels of Ab after one month compared to controls (1217[747-1887]BAU/mL vs. 1477[942-2556]BAU/mL, p = 0.002), even after correction for age and gender (p = 0.002). No difference was found between subjects with T1D and T2D. After 6 months, antibody levels significantly decreased in people with and without diabetes, with no differences between groups, although some subjects were lost at follow-up. In subjects with diabetes, only a significant correlation was found between Ab level and renal function (rho 0.190, p = 0.042).Both T1D and T2D are associated with a reduced early response to vaccination. The serum concentration of Ab significantly reduced over time in both groups, highlighting the relevance of vaccination boosters independently of the presence of diabetes.

Purpose: Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues. So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-existing diabetes’s pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology. Results: SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand the long-term consequences that will affect patients with diabetes who survived COVID-19. Conclusions: Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus’s detrimental effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features, supporting a potential role of COVID-19 in the development of diabetes.

In the past, indications for total pancreatectomy (TP) were rare, with several concerns about patients’ postoperative quality of life due to exocrine and endocrine post-pancreatectomy management [...]

Introduction: Thyroid ultrasound (US) is crucial for clinical decision in the management of thyroid nodules. In this cross-sectional study, we aimed to test if the evaluation of thyroid nodules’ vascularization could improve the risk stratification ability of the American College of Radiology (ACR) TI-RADS classification system. Methods: A total of 873 thyroid nodules undergoing fine-needle aspiration were classified according to ACR TI-RADS US classification. Three types of vascularization were identified: type 0, no vascular signals; type 1, peripheral vascular signals; type 2, peripheral and intralesional vascular signals. Cytology specimens were evaluated conforming to the Italian Reporting System for Thyroid Cytology, and TIR3b, TIR4, and TIR5 were defined as high risk for malignancy. Odds ratios (ORs) with 95% confidence intervals (CI) and the areas under the receiver operating characteristic curves (ROC-AUC) for high-risk cytology categories were calculated. Results: The 3 vascular patterns were differently distributed within the cytology categories: 52.4% of TIR1c, 15.9% of TIR2, 5.9% of TIR3a, 6.7% of TIR3b, 12.5% of TIR4, and 28.9% of TIR5 nodules had no vascular signals (p < 0.001). Nodule vascularity alone was not associated with a higher risk of malignant cytology (OR [95% CI] 0.75 [0.43–1.32], p = 0.32), without differences between peripheral (OR [95% CI] 0.65 [0.35–1.20]) and intranodular (OR [95% CI] 0.88 [0.48–1.62]) vascularization (p = 0.22). The ROC-AUC (95% CI) for the diagnosis of malignant cytology was similar when considering TI-RADS classification alone (0.736 [0.684–0.786]) and when considering TI-RADS classification plus the presence/absence of vascular signals (0.736 [0.683–0.789], p value for differences between the ROC-AUCs: 0.91). Among TR1, TR2, and TR3 TI-RADS classes, no nodules without vascular signals showed a malignant cytology, allowing the identification of nodules with benign cytology with 100% specificity within these US classes. Conclusions: Color Doppler study of thyroid nodules does not improve the risk stratification ability of the ACR TI-RADS US classification system.

Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status.We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837.Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbAAt diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes.European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).

Patients with diabetes have a prothrombotic state and a 2 to 4 times higher risk of cardiovascular events than those without diabetes. Aspirin is the cornerstone of treatment in patients withcardiovascular disease, irrespective of diabetes status, being able to confer a 19% relative risk reduction per year in serious vascular events compared with placebo at long-term follow-up (6.7% vs 8.2% per year, p 0.0001). Data regarding the benefit-risk ratio of aspirin prescribed to patients with diabetes without established cardiovascular disease are less convincing, especially when compared to other preventive strategies. Of note, in primary prevention trials, aspirin allocation yielded a significant 12% proportional reduction in serious vascular events, irrespective of diabetes status, corresponding to a small annual absolute risk reduction (0.06% per year). However, in everyday clinical practice aspirin is still largely prescribed by both diabetologists and cardiologists. In this article, we provide eight questions and answers corroborated by available evidence on the use of aspirin for primary prevention of cardiovascular disease in diabetes.

Immunotherapies for type 1 diabetes mellitus (T1D) have been the focus of intense research over the past few decades. Nevertheless, the results of clinical trials have not matched expectations. However, thanks to the recent and promising results on T1D prevention, among all the different immune-intervention strategies, clinical evidence on anti-CD3 monoclonal antibodies (mAb) deserves particular attention and in-depth evaluation.In this narrative review, we introduce the role of T-cells and their co-receptor CD3 in the pathogenesis of T1D and examine the potential of anti-CD3 mAbs as a treatment for preventing or curing T1D. We discuss pre-clinical studies and phase II/III clinical trials testing the anti-CD3 mAb teplizumab in subjects at T1D high risk, and testing teplizumab and otelixizumab in T1D recent onset patients. In this work, we discuss the current evidence gathered on anti-CD3 therapy to offer insights on the treatment strengths, limitations, and unmet needs.Recent phase II clinical trials with teplizumab in individuals at high-risk of developing T1D seem encouraging, but benefits associated with the use of anti-CD3 mAb in recent-onset T1D are still controversial. A better patient selection, based on immunological profiles and specific biomarkers, is crucial to improve clinical outcomes in T1D immunotherapies.

To build a clinical risk score to aid risk stratification among hospitalised COVID-19 patients.The score was built using data of 417 consecutive COVID-19 in patients from Kuwait. Risk factors for COVID-19 mortality were identified by multivariate logistic regressions and assigned weighted points proportional to their beta coefficient values. A final score was obtained for each patient and tested against death to calculate an Receiver-operating characteristic curve. Youden's index was used to determine the cut-off value for death prediction risk. The score was internally validated using another COVID-19 Kuwaiti-patient cohort of 923 patients. External validation was carried out using 178 patients from the Italian CoViDiab cohort.Deceased COVID-19 patients more likely showed glucose levels of 7.0-11.1 mmol/L (34.4%, p 0.0001) or11.1 mmol/L (44.3%, p 0.0001), and comorbidities such as diabetes and hypertension compared to those who survived (39.3% vs. 20.4% [p = 0.0027] and 45.9% vs. 26.6% [p = 0.0036], respectively). The risk factors for in-hospital mortality in the final model were gender, nationality, asthma, and glucose categories (5.0, 5.5-6.9, 7.0-11.1, or 11.1 mmol/L). A score of ≥5.5 points predicted death with 75% sensitivity and 86.3% specificity (area under the curve (AUC) 0.901). Internal validation resulted in an AUC of 0.826, and external validation showed an AUC of 0.687.This clinical risk score was built with easy-to-collect data and had good probability of predicting in-hospital death among COVID-19 patients.

Aim To evaluate early, before the onset of cardiovascular events and of chronic renal insufficiency, the association between chronic kidney disease (CKD)-mineral bone disorder (MBD) biomarkers and vascular stiffness [Cardio Ankle Vascular Index (CAVI)] in the course of type 2 diabetes (T2DM). Method We evaluated 174 T2DM patients [median age 56 years; male/female (M/F) 100/74] with diabetes duration Results Albumin-to-creatinine ratio (ACR) averaged 8.5 mg/g (5.6-17.2) with 12.6% of the patients showing pathologic values, indicative of incipient diabetic nephropathy. Serum parathyroid hormone, fibroblast growth factor 23, and sclerostin were higher while 1,25-dihydroxyvitamin D and Klotho were lower than a control group. CAVI was normal ( Conclusion In the absence of overt cardiovascular disease and of chronic renal insufficiency, CAVI is frequently pathologic in T2DM. DBP and ACR are modifiable risk factors of vascular stiffness in T2DM, thus warranting optimal assessment.

The relation between diabetes mellitus (DM) and bleeding complications after percutaneous coronary intervention (PCI) is controversial. This study investigates the role of low platelet reactivity (LPR) in the bleeding risk stratification of patients who underwent PCI according to DM status. A total of 472 patients who underwent PCI on aspirin and clopidogrel were included retrospectively. Platelet reactivity was assessed using the VerifyNow P2Y(12) assay. LPR was defined as platelet reactivity unit ≤178. The primary end point was the occurrence of any bleeding at 5 years stratified by DM status and LPR. DM was present in 30.5% of patients. LPR was less frequent in patients with DM (p = 0.077). Overall, 11.9% of patients experienced a bleeding complication at 5 years. The incidence of bleeding did not differ in subjects with and without DM (p = 0.24). LPR had a similar value for stratifying the increased bleeding risk in patients with and without DM (interaction p between DM and LPR 0.69). A stepwise increase in the crude rates of bleeding complications was observed across patients with and without LPR and DM (log-rank p = 0.004), with those affected by both conditions having the highest crude incidence rate. In conclusion, on top of aspirin, approximately 1/3 of patients who underwent PCI on clopidogrel have LPR. Assessment of LPR provides a significant incremental value for predicting bleeding irrespective of DM status. Although the presence of DM per se does not increase the incidence of hemorrhagic complications, the coexistence of DM and LPR identifies the subgroup with the highest bleeding risk.

Heart failure (HF) represents a major global health and economic burden with still unacceptably high morbidity and mortality rates. In recent decades, novel therapeutic opportunities with a significant impact on HF outcomes have been introduced in addition to angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and mineralocorticoid receptor antagonists. These include drugs such as ivabradine, sacubitril–valsartan, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors. The availability of an extremely large pharmacological armamentarium to face this chronic global disease highlights the importance of assessing cost effectiveness to promote sustainable healthcare. In light of the recent approval of SGLT-2 inhibitors for the treatment of HF with reduced ejection fraction, including in individuals without type 2 diabetes mellitus, the aim of this review was to provide an updated comparative evaluation of the efficacy and cost effectiveness of different pharmacological treatments for the prevention (stage A) and treatment of asymptomatic (stage B) and symptomatic (stages C–D) left ventricular dysfunction.

Background: This is a proof of concept, as a pilot study, with the aim to evaluate continuous glucose monitoring metrics (CGM) in subjects with type 2 diabetes (T2DM), treated with nutritional therapy and metformin, before and after testosterone replacement therapy (TRT). Methods: In this longitudinal observational study, subjects affected by T2DM and starting TRT for documented ED and hypogonadism were enrolled. All subjects mounted a CGM system during the v0 visit, one week before the beginning of the TRT (week−1), during v2, four weeks after the start of TRT (week 4), and v4 (week 12). CGM was worn for about 144 h after each visit. Results: A total of seven patients, referring to our clinic for erectile dysfunction (ED), were studied (aged 63.3 ± 2.3 years). Mean (± standard deviation) total testosterone level was 2.3 ± 0.6 ng/mL at baseline. After TRT, total testosterone level was 4.6 ± 3.04 ng/mL at week 4 and 3.93 ± 4.67 ng/mL at week 12. No significant differences were observed in TIR, TAR, TBR, estimated HbA1c, AUC below, and AUC above limit during the intervention period. Conclusions: This is the first study evaluating the effects of TRT on daily glucose excursions in subjects with T2DM and hypogonadism. Though we did not find any significant difference in key CGM metrics during the 12 weeks of TRT, this study confirms the glycometabolic safety of the TRT even on the most novel standardized glycemic targets.

Hyperglycemia has been evaluated extensively as risk factors for cardiovascular disease (CVD) in people with type 1 diabetes (T1DM). However, the effects of the autoantibody on atherosclerosis and immunogenic trigger are not well understood in T1D. Using the generated several mice models of atherosclerosis including NOD, congenic ApoE-/-/NOD (NDM and no- autoimmune), ApoE-/-/NOD (autoimmunity with insulitis, NDM) and ApoE-/-/NOD autoimmune DM mice, we analyzed immune cells composition of aorta and have observed the increasing numbers of CD3+(CD3+/CD25-), Th1 and Th17 subset of T cells and B cells and decreased Treg (CD3+/CD25+/Foxp3+) in the ApoE-/-/NOD and ApoE-/-/NOD-DM mice vs. control. In addition, we postulate that the identification of specific autoantibody(s) which induce dysregulaton of T-cells, resulting in enhancing its infiltration and accumulation at the plaques could aid new immunotherapies for atherosclerosis. Here we performed autoantigen microarrays to profile and identify specific autoantibodies, enhancing the severe atherosclerosis in subgroups of Medalist patients with chronic duration of T1D due to autoimmunity with positive HLA DR3/4 risk alleles and autoantibodies and compared to the people with monogenic diabetes lacking HLA DR3/4 risk alleles for T1D and autoantibodies. Autoantigen microarrays from the plasma of T1D patients with positive DR3/4 risk and CVD identified 8 autoantibodies changed in the context of atherosclerosis, compared to the people with monogenic diabetes. To confirm the autoantibody profiling data from the patients, we analyzed the autoantibody profiles in the T1D mice models of atherosclerosis described above. Autoantigen microarrays analysis of the plasma of T1D patients and mice showed several common findings that reached significance anti-Nucleolin Ab, p=0.005. These findings indicate autoimmunity may contribute to the progression of atherosclerosis in T1D. Further studies are in progress to replicate these findings in other cohorts of T1D. Disclosure K. Park: None. Q. Li: None. H. Park: None. J. Fu: None. S. Kissler: None. E. Maddaloni: Research Support; Self; European Foundation for the Study of Diabetes, Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck KGaA. I. Wu: None. A. H. Lichtman: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc. Funding DK036836, DK036836, EY026080

Il diabete mellito di tipo 2 (DM2) e una patologia multifattoriale altamente prevalente nella popolazione anziana. Piu del 65% della popolazione affetta da DM2 ha infatti un’eta maggiore di 65 anni ed esiste uno stretto legame fisiopatologico e clinico tra invecchiamento, DM2 e complicanze vascolari. Cio impone un’attenta riflessione sui rischi e benefici delle numerose opportunita terapeutiche oggi a disposizione per la cura del DM2. Gli obiettivi terapeutici e le scelte farmacologiche devono essere personalizzati sulla base del grado di complessita del paziente.

Contrasting data have been published about the impact of cardiovascular disease on Covid-19. A comprehensive synthesis and pooled analysis of the available evidence is needed to guide prioritization of prevention strategies. To clarify the association of cardiovascular disease with Covid-19 outcomes, we searched PubMed up to 26 October 2020, for studies reporting the prevalence of cardiovascular disease among inpatients with Covid-19 in relation to their outcomes. Pooled odds-ratios (OR) for death, for mechanical ventilation or admission in an intensive care unit (ICU) and for composite outcomes were calculated using random effect models overall and in the subgroup of people with comorbid diabetes. Thirty-three studies enrolling 52,857 inpatients were included. Cardiovascular disease was associated with a higher risk of death both overall (OR 2.58, 95% confidence intervals, CI 2.12–3.14, p p p = 0.34, number of studies 4). Four out of five studies reporting OR adjusted for confounders failed to show independent association of cardiovascular disease with Covid-19 deaths. Accordingly, the adjusted-OR for Covid-19 death in people with cardiovascular disease dropped to 1.31 (95% CI 1.01–1.70, p = 0.041). Among patients hospitalized for Covid-19, cardiovascular disease confers higher risk of death, which was highly mitigated when adjusting the association for confounders.

In type 2 diabetes, anti-thrombotic management is challenging, and current anti-platelet agents have demonstrated reduced efficacy. Old and new anti-diabetic drugs exhibited—besides lowering blood glucose levels—direct and indirect effects on platelet function and on thrombotic milieu, eventually conditioning cardiovascular outcomes. The present review summarizes existing evidence on the effects of glucose-lowering agents on platelet properties, addressing pre-clinical and clinical research, as well as drug–drug interactions with anti-platelet agents. We aimed at expanding clinicians’ understanding by highlighting new opportunities for an optimal management of patients with diabetes and cardiovascular disease. We suggest how an improvement of the thrombotic risk in this large population of patients may be achieved by a careful and tailored combination of anti-diabetic and anti-platelet therapies.

A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis. Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis. A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011). Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

In a nationwide study of 3818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 inhibition in COVID-19 development and progression.

Aim To assess the effect of the coronavirus disease 2019 (COVID‐19) lockdown on glycaemic control in subjects with type 2 diabetes (T2D). Materials and Methods In this observational, multicentre, retrospective study conducted in the Lazio region, Italy, we compared the differences in the HbA1c levels of 141 subjects with T2D exposed to lockdown with 123 matched controls with T2D who attended the study centres 1 year before. Basal data were collected from 9 December to 9 March and follow‐up data from 3 June to 10 July in 2020 for the lockdown group, and during the same timeframes in 2019 for the control groups. Changes in HbA1c (ΔHbA1c) and body mass index (ΔBMI) during lockdown were compared among patients with different psychological well‐being, as evaluated by tertiles of the Psychological General Well‐Being Index (PGWBS). Results No difference in ΔHbA1c was found between the lockdown and control groups (lockdown group −0.1% [−0.5%−0.3%] vs. control group −0.1% [−0.4%−0.2%]; p = .482). Also, no difference was found in ΔBMI (p = .316) or ΔGlucose (p = .538). In the lockdown group, subjects with worse PGWBS showed a worsening of HbA1c (p = .041 for the trend among PGWBS tertiles) and BMI (p = .022). Conclusions The COVID‐19 lockdown did not significantly impact glycaemic control in people with T2D. People with poor psychological well‐being may experience a worsening a glycaemic control because of restrictions resulting from lockdown. These findings may aid healthcare providers in diabetes management once the second wave of COVID‐19 has ended.

AIMS Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type. METHODS In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders. RESULTS Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p

Aims To evaluate whether subjects with diabetes hospitalized for Coronavirus disease-19 (Covid-19) represent a subgroup of patients with high-risk clinical features compared to patients with diabetes without Covid-19. Methods In this case-control study 79 patients with type 2 diabetes out of 354 adults hospitalized for Covid-19 and 158 controls with type 2 diabetes but without Covid-19, matched for age and gender, were enrolled. Medical history and concomitant therapies were retrieved from medical charts and compared between cases and controls, controlling for confounders. Results Fully-adjusted multivariate logistic regression model showed that previous CVD history did not differ between patients with and without Covid-19 (odds ratio 1.40, 95% confidence interval [CI]: 0.59-3.32, p=0.45). A higher prevalence of chronic obstructive pulmonary disease (COPD) (OR 3.72, 95%CI: 1.42-9.72, p=0.007) and of chronic kidney disease (CKD) (OR 3.08, 95%CI: 1.18-8.06, p=0.022) and a lower prevalence of ever smokers (OR 0.30, 95%CI: 0.13-0.67, p=0.003), of users of lipid lowering agents (OR 0.26, 95%CI: 0.12-0.54, p